Novel process for the preparation of 9beta, 11beta-oxido derivatives of steroid compounds



United States Patent Ofilice s ass 1ss NOVEL PROCESS FOR 'rnn PREPARATION OF sans-x100 DERIVATIVES OF STEROID No Drawing. Filed Apr. 25 I963, Ser. No. 275,536 20 Claims. (Cl. 260239.55)

This invention is concerned with a novel process for the preparation of 9fl,llp-epoxy steroids. More particularly, this invention relates to an improved process for the preparation of 91.3,l1fl-epoxy steroids by the treatment of the corresponding 9a-bromo-l lp-hydroxy steroid with potassium fluoride in a substantially neutral medium.

It has long been known that such 9-halo-ll-hydroxy steroids as 9a-fluorocortisone, 9a-fluorohydrocortisone, 9afiuoroprednisone and 9a-fluoroprednisolone and the.l6aand l6p-methyl and 2l-ester derivatives thereof display anti-inflammatory activity far greater than that afforded by the corresponding 9-des-halo compounds. Heretofore, preparation of these and other therapeutically active 9-halo-1l-hydroxy steroids has involved the conversion of 9a-bromo-l 1,8-hydroxy intermediates to the corresponding 9p,1lfl-epoxide by treatment of the bromohydrin Ill-esters with alkalis, such as sodium acetate in-acetone, or alkali bases, such as sodium hydroxide and sodium methoxide in methanol. Conversion of the epoxide to the desired halohydrin is subsequently accomplished with hydrogen halide. Epoxide formation by the conventional process, however, has not proved entirely satisfactory since treating the bromohydrin at reflux in an alkaline medium often results in undesired side reactions such as, for example, hydrolysis of ester groupings at other positions in the steroid nucleus, D homoannulation of the D-ring and rearrangement and degradation of the cortical side-chain.

By employing the process of the instant invention, the possibility of such undesired side reactions is substantially eliminated. Accordingly, it is the object of this invention to provide an improved process for the conversion of a 9a-bromo-llphydroxy steroid into the corresponding 9:3,llfi-epoxide. It is a further object of this invention to provide an improved method for the preparation of 9p,lIp-epoxy steroids from the corresponding 9a-bromollfl-hydroxy intermediates wherein the bromohydrin is treated with potassium fluoride in a substantially neutral medium under conditions which result in the formation of the epoxide in high and relatively pure yield.

The instant invention is based upon the discovery that by treating a 9a-bromo-llfl-hydroxy steroid such as, for example l6-methyl-9-br0m0-l ,4-pregnadiene-l lfi, 17a,

I 2l-triol-3,20-dione 2l-acetate with potassium fluoride in either a S,S-disubstituted sulfoxide on a N,N-disubstituted amide, the corresponding 95,1 lB-epoxide (i.e., lfia-methyl- 9fl,llfi-oxido-l,4-pregnadiene-l7,21-diol-3,20-dione Zlacetate) is formed in high and relatively pure yield.

By the term, S,S-disubstituted sulfoxide is meant S,S-dilower alkyl sulfoxides, including straight and branched chain isomers, such as, for example, dimethylsulfoxide wherein the lower alkyl moiety contains from 1 to 4 carbon atoms and cycle-lower alkyl sulfoxides such as, for example, tetra-hydrothiophenc sultoxide wherein the cycle-lower alkyl moiety contains from 4 to carbon atoms. By the term, N,N-disubstituted amide, is meant N,N-di-lower alkyl formamides and N,N-di-lower alkyl aoetamides, including straight and branched chain isomers, such as, for example, dimethylformamide or diethylacetamide wherein the lower alkyl moiety contains from t to 2 carbon atoms; N-lower alkyl-e-pyrrolidones, including straight and branched chain isomers, such as, for example, N-methyl-e-pyrrolidone, wherein the lower alkyl moiety 3,255,185 Patented June 7, 1966 contains from I to 2 carbon atoms; and N-lower alkyl-apiperidones, including straight and branched chain isomers, such as, for example, N-ethyl-a-pyrrolidone, wherein the lower alkyl moiety contains from I to 2 carbon atoms.

The quantity of potassium fluoride used in the process of this invention must be at least two moles per mole of steroid, the preferred ratio being about our moles of potassium fluoride to one mole of steroid. Because of the limited solubility of potassium fluoride in the solvents of this process, the volume of solvent per mole of potassium fluoride, though subject to tion temperature, is a critical factor. The minimum amount of solvent which can be used per mole of steroid is about five liters; the preferred ratio being about ten liters of solvent per mole of steroid. The temperature range over which the reaction may be carried out i l depend upon the solvent employed. In general, the tion temperature may vary from a minimum of about 25' C. up to the reflux temperature of the solvent. It is desirable, however, to keep the reaction temperature below 100' C.; the preferred temperature range being from to 90 C.

In general, the preferred method process of this invention is to heat a mixture of one mole of Qez-bl'OtllO-l lfl-hydroxy steroid and four moles of potassium fluoride in ten liters of solvent (e.g., dimethylsul- {oxide or dimethylformamide) at about 90' C. for ap proximately 8 hours. The reaction mixture is then poured into ice water and the crude epoxide is recovered by filtration. Purification is effected by recrystallization in the usual manner from such organic solvents and solvent mixtures such as acetone, acetone-hexane, ethyl acetatehexane, etc.

If, in the process described above, only five liters of solvent are used for the same quantity of steroid, very little epoxide will be formed after heating at 90' C. for only 8 hours. Under these conditions, the reaction may require about 72 hours to go to completion. As a further example, one mole of steroid and 2 moles of potassium fluoride in 30 liters of solvent at room temperature takes about 48 hours to go to completion. The optimum reaction time which varies from 4 to 72 hours depends upon the temperature, the relative concentration of steroid, amount of potassium fluoride and solvent.

The process of the instant invention is one of general applicability and may be used to convert any 9a-bromollfl-hydroxy steroid into the corresponding 9.1,1 lp-epoxy compound. The 9a-bromo-l lfl-hydroxy starting materials and the methods for their prepartion are, of course, well known in the art.

The following examples are set forth as further and more particular illustrations of the process of the instant invention. No limitation, however is intended except as defined in the appended claims.

Example 1 Mix 15 g. of l6a-methyl-9a-bromo-l,4-pregnadiencl1fl,l7,21-triOl-3,20-dione ZI-acetate, 300 ml. of d methylsult'oxide and 6.6 g. of potassium fluoride. Stir the reaction mixture at -90 C. for 7-8 hours and pour into about 1.5 l. of ice water with continued stirring. Recover the crude l6a-methyl-9p,llp oxido-l,4pregnadiene-lle,2l-diol-3,20 dione, 2l-acetate by filtration and purify by recrystallization from ethyl acetate-hexane.

Example 2 Mix 2.5 g. of l6a-methyl-9a-bromo-l,4-pregnadiene- 1lfl,l7a,2l-triol-3,20-dione 2l-acetate, 1.1 g. of potassium fluoride and H10 mL of dimethylformamide. Stir at C. for about [6 hours. Recover and purify the epoxide as in Example 1.

variation with the reacof carrying out the 3 Example 3 Stir a mixture of 2.5 g. of I6-methyl-9-bromol,4- pregnadiene-l1p,l7,21-1riol-3,20 dione 2l-acetate, -55 g. of potassium fluoride and 150 m1. of dimethylsulfoxide at 25' C. for about '48 hours. Recover and purify the epoxide as in Example 1.

Example 4 Heart to 85-90 C. with stirring a mixture of 15 g. of 16 methyl 9ar-bt'0m0-L4-pl'egnadiene-1 l p,l7,2l-triol- 3,20-dione 21-acetate, 300 ml. of dimethylacetamide and 6.6 g. of potassium fluoride. Continue stirring at this temperature for 7-8 hours. Recover and purify' the epoxide as in Example 1.

Example 5 Mix 4.85 g. of 9-bromo-4-pregnene-llp,l7,2l-triol- 3,20-dione 2l-acetate, 2.32 g. of potassium fluoride and 100 ml. of dimethylsulfoxide. Heat to about 90 C. and stir for 7-8 hours. Pour the reaction mixture into approximately 1.5 I. of ice water with continued stirring and separate the crude 9fl,l lfi-oxido-4-pregnene-l7,2ldiol-3,20-dione ZI-aoetate by filtration. Purify by recrystallization from acetone.

Example 6 Employ the process of Example'S, substituting for the dimethylsulfoxide solvent 100 ml. of diethylsult'oxide, to prepare 9 3,115 oxido-4-pregnene-17,2l-diol-3,20-dionc Zl-acetate.

Example 7 Employ theprocess of Example 5, substituting for the dimethylsulfoxide solvent 100 ml. of diethylformamidc, to prepare 913,1Ifl-oxidoM-pregnane-l7,2l-diol-3,20- dione ZI-acetate.

Example 8 Stir a mixture of 3.82 g. 9a-bromo-4-androstene-l lfi-ol- 3,17-dione, 2.32 g. of potassium fluoride and 100 ml. of dimethylformamide at 90 C. for 8 hours. Pour the reaction mixture into about 1.5 ml. of ice water with continued stirring. Separate the crude 9,6,11,8-oxido-4- androstene-3,17-dione by filtration and purity by recrystallizatiorr from acetone-petroleum ether. I

Example 9 Employ the process of Example 9, substituting for the dimethylforrnamide solvent 100 ml. of diethylacetamide, to prepare 913,1lfl-oxido-4-androstene-3,l7-dione.

Example 10 Employ the process of Example 9, substituting for the dimethylforrnamide solvent 100 ml. of N-methyl-e-pyrrolidone, to prepare 95,1Ip-oxidot-androstene-Il,l7-

dione.

Example 11 Example 12 Employ the process of Example ll, substituting for the N-ethyli-pyrrolidone solvent 100 ml. of N-methyl-apiperidone, to prepare 95,1lp-oxido4-pregnene-l7a,2ldiol-3,20-dione.

Example 13 Employ the process of Example 12, substituting for the N-ethyl-a-pyrrolidone solvent 100 ml. of N-ethyl-a-piperidone, to prepare 95,1lfi-oxidol-pregncne-l7,21-diol- 3,20-dione.

4 Example 14 Example I 5 Employ the process of Example 14, substituting for the dimethylsulfoxidc solvent 100 ml. of tetrahydrothiophene sulfoxide, to prepare 16fl-methyl-9fl,1lp-oxido l,4- nadiene-17a,2l-diol-3,20-dione.

The subject matter which applicant regards as his i vention is particularly pointed out and distinctly claimed as follows:

1. The process for the conversion of a 9-bromo-llphydroxy steroid into the corresponding 9p,ilp-epoxide which comprises treating said 9 btOm0-llfi-hydrOXy steroid with at least 2 moles of potassium fluoride per mole of steroid in at least five liters per mole of steroid of a solvent selected from the group consisting of S,S-dilower allryl sulfoxides wherein the lower alkyl moiety contains from '1 to 4 carbon atoms, cyclo-lower alkyl sult'oxides wherein the cyclo-lower alkyl moiety contains from 4 to 5 carbon atoms, N,N-di-lower alkyl formamides and N,Ndi lower allryl acetamides wherein the loweralkyl moiety contains from I to 2 carbon atoms, and N- lower alkyl-a-pyrroliddnes and N-lower alkyI-wpiperI- dones wherein the lower allryl moiety contains from 1 to 2 carbon atoms at a temperature of about 25 to 100' C.

2. The process of claim 1 wherein the solvent is dimethylsulfoxide.

3. The process of claim 1 wherein the solvent is diethylsulfoxide.

4. The process of claim I wherein the solvent is dimethylformamide.

5. The process of claim 1 wherein the'solvent is diethylformarnide.

6. The process of claim 1 wherein the solvent is dimethylaeetamide.

7. The process of claim 1 wherein the solvent is diethylacetamide.

8. The process of claim 1 wherein the solvent is N- methyl-a-pyrrolidone.

9. The process of claim 1 wherein the solvent is N- methyl-a-piperidonc.

10. The process of claim 1 wherein the solvent is tetrahydrothiophene sulfoxide.

11. The process for the conversion of a Qa-bromo-llfihydroxy steroid into the corresponding QflJIfi-epoxrde which comprises treating said 9a-bromo-lip-hydroxy steroid with about 4'rnoles of potassium fluoride per mole of steroid in about 10 liters per mole of steroid of a solvent selected from the group consisting of S,S-di-lower alkyl sulfoxides wherein the lower alkyl moiety contains from 'i to 4 carbon atoms, cyclo-lower alkyl sulfoxrdes wherein the cycle-lower alkyl moiety contains from 4 to 5 carbon atoms, N,N-di-lower alkyl formamides and N. N-di-lower alkyl acetarnides wherein the lower alkyl morety contains from i to 2 carbon atoms, and NJower alkyla-pyrrolidones and N-lower alkyl-a-piperidones wherein the lower alkyl moiety contains from 1 to 2 carbon atoms at a temperature of from 75 to C.

12. The process of claim 11 wherein the solvent 15 dimethylsulfoxide.

13. The process of claim 11 wherein the solvent ts dlethylsulioxide.

14. The process of claim 11 wherein the solvent rs drmethylformamide.

15. The process of claim ll wherein the solvent rs diethylforrnamide.

16. The process of claim 11 dimethylacetamide.

17. The process of claim 11 diethylacetamide.

18. The process of claim 11 N-methyl-a-pyrrolidone.

19. The process of claim 11 N-methyl-a-piperidone.

wherein the wherein the wherein the wherein the solvent is solvent is solvent is 5 solvent is No references cited.

LEWIS GO'ITS, Primary Examiner. T. MESHBESHER, Assistant Examiner. 

1. THE PROCESS FOR THE CONVERSION OF A 9A-BROMO-11BHYDROXY STERNOID INTO THE CORRESPONDING 9B, 11B-EPOXIDE WHICH COMPRISES TREATING SAID 9A-BROMO-11B-HYDROXY STEROID WITH AT LEAST 2 MOLES OF POTASSIUM FLUORIDE PER MOLE OF STEROID IN AT LEAST FIVE LITERS PER MOLE OF STEROID OF A SOLVENT SELECTED FROM THE GROUP CONSISTING OF S,S-DILOWER ALKYL SULOXIDES WHEREIN THE LOWER ALKYL MOIETY CONTAINS FROM 1 TO 4 CARBON ATOMS, CYCLO-LOWER ALKYL SULFOXIDES WHEREIN THE CYCLO-LOWER ALKYL MOIETY CONTAINS FROM 4 TO 5 CARBON ATOMS, N,N-DI-LOWER ALKYL FORMAMIDES AND N,N-DI-LOWER ALKYL ACETAMIDES WHEREIN THE LOWERALKYL MOIETY CONTAINS FROM 1 TO 2 CARBON ATOMS, AND NLOWER ALKYL-A-PYRROLIDONES AND N-LOWER ALKYL-A-PIPERDONES WHEREIN THE LOWER ALKYL MOIETY CONTAINS FROM 1 TO 2 CARBON ATOMS AT A TEMPERATURE OF ABOUT 25 TO 100*C. 